April
7, 1999. Grapefruit have been valued as part of an anti-prostate cancer
diet along with tomatoes and strawberries. Red-fleshed grapefruit contains
lycopene, an antioxidant that appears to help prevent prostate cancer.
And citrus fruit compounds, as reported below,
may have immune-boosting and anti-cancer effects.

But substances in grapefruit have quite
powerful effects on the body's absorption of many widely-prescribed medications.
New evidence suggests that consuming grapefruit juice could interfere
with a chemotherapy drug used for prostate cancer, Vinblastine.

From Blood Pressure Drugs to Chemo

Drinking a glass of grapefruit juice when
taking certain medications has long been known to help the body absorb
the drug. This "grapefruit effect" is distinct from the need
for acidity to dissolve some tablets such a Nizoral (ketoconazole). If
you've been advised to drink orange juice along with Nizoral, you should
of course continue to follow your doctor's instructions.

A couple of years ago, studies showed that grapefruit
improves absorption of drugs including calcium channel blockers and HIV-protease
inhibitors. Now comes another twist. Grapefruits vary according to how
and where they're grown. The state of people's innards varies. More than
one set of intestinal chemicals is involved. And depending on the drug,
the "grapefruit effect" could either boost it or block it.

The latest study has found that grapefruit
blocks absorption of some drugs. One of the drugs blocked,
Vinblastine, is used in chemotherapy for prostate cancer. Scientists at
the University of California at San Francisco (UCSF) reported last week
that laboratory tests on cells show that grapefruit juice may have a negative
impact on the body's absorption of many widely-prescribed medications
including Vinblastine.

Bombers in a Glass of Juice, Potent Metabolic Effects

The grapefruit effect was discovered by
happy chance almost a decade ago when scientists gave volunteers grapefruit
juice to mask the taste of a medication. A single glass can significantly
increase the absorption of a number of commonly used oral medications
including nearly all calcium channel blockers (used to control blood pressure),
some sedatives, and some immunosuppressants and protease inhibitors (used
for transplants and to treat AIDS).

How the grapefruit effect works was unknown
until Dr. Paul Watkins and colleagues at the University of Michigan Medical
Center in Ann Arbor reported in May 15 1997 Journal of Clinical Investigation
that grapefruit juice decreases the amount of an enzyme, called CYP3A4,
already known to be present in the small intestine.

This narrowed the search for substances
in grapefruit juice that affect drug metabolism. Pinpointing these could
enable manufacturers to produce safer and more effective medications.

Dr. Watkins went on to isolate a pair of
substances in grapefruit that do this. In the November 1997 issue of Drug
Metabolism and Disposition, he and his UM colleagues reported that
these two components act like suicide bombers, attaching themselves to
the CYP3A4 and stopping it from interfering with drug absorption.

After taking grapefruit juice, everyone
in the study had virtually the same level of CYP3A4. Normally, indivuals
vary in how much CYP3A4 their intestines churn out. This normal variation,
by affecting metabolism of drugs, impacts drug safety. A dose that is
right for one individual can be ineffective or even toxic to another.
The researchers were excited to realize that adding the active substance
in grapefruit to a medication could produce a drug for which a standard
dosage would be equally effective in everyone.

But not only are people's guts variable
-- so are grapefruits. The concentration of the active ingredients varies
dramatically among grapefruits and grapefruit juices, even within the
same product line. This is most likely, the researchers say, because of
growing conditions in different regions and because manufacturers typically
buy their grapefruits from many areas. "For this reason," Watkins said
in November 1997, "it would be preferable to add the active ingredient
to pills, rather than just taking medication with grapefruit products."

Asked what people who regularly take drugs
that are metabolized by CYP3A4 should do about grapefruit in their diet,
Dr. Lown said, "Consistency is the key." "If you regularly drink grapefruit
juice, don't change. If you are on these drugs and don't normally take
them with grapefruit juice, you may need to consult your physician before
adding grapefruit juice to your diet."

New Caution Over Blocking Interaction

In the latest study, published in the April
1999 issue of Pharmaceutical Research, Dr. Andrea Soldner and other
scientists at UCSF show that grapefruit juice can actually inhibit the
body's absorption of certain drugs including:

Vinblastine (for combating cancer)

Cyclosporine (for supressing organ rejection following transplant)

Losartan (for controlling high blood pressure)

Digoxin (for treating congestive heart failure)

Fexofenadine (for alleviating allergy symptoms)

This blocking of drug activity occurs because an unknown substance in grapefruit
juice activates a naturally-produced chemical, P-glycoprotein, in the intestinal
tract. When grapefruit juice interacts with P-glycoprotein, the result is
an increased likelihood that certain drugs will be stopped from entering
the bloodstream.

"These findings help to clarify some
major discrepancies we've noticed in the impact of grapefruit juice on various
types of medications," said Dr. Leslie Benet, professor of Biopharmaceutical
Sciences at UCSF and director of the study. Patients already taking grapefruit
juice with their medications can continue to do so, he said. But patients
on drugs identified as specifically affected by this blocking effect, "
may get a further increase in absorption by taking their drugs a couple
of hours after a glass of grapefruit juice."

According to Dr. Benet, patients who have
not previously taken their drugs with grapefruit juice "should be very
cautious in doing so, since we now recognize, depending on the drug, that
grapefruit juice may either increase or decrease levels of drug in the blood,
leading to potential concerns for toxicity or lack of efficacy."

Citrus Limonoids May Have Anti-Cancer Effects

Posted April 7, 1999. Limonoids, found in the skin of citrus fruits,
could have significant health benefits, scientists said last month at the
American Chemical Society conference. Limonoids may have anti-cancer effects.

Limonoids are compounds found in citrus fruits,
usually in the peels. They produce the bitter taste and zesty aroma. Citrus
limonoids are present in commercial orange juice at about the same level
as vitamin C.

Some researchers think citrus limonoids may
be responsible for health effects previously attributed to vitamin C. A
Japanese company, Wakayama Prefectual Federation of Agricultural Co-operatives,
is making an orange juice with triple the level of limonoid glucosides.

Preliminary research found limonoids could
prevent and halt cancer under laboratory conditions. They had anti-cancer
effects in animals and prevented the spread of human breast cancer in a
cell culture. Scientists are now exploring their use more fully.

The effect in the human body and on other
types of cancer has not yet been tested. So far the work has progressed
from cells to mice, the researchers reported at the conference. Another
team is testing the performance of 12 limonoids in preventing cancer in
humans.